Dataset Information

Multiple microRNAs within the 14q32 cluster target the mRNAs of major type 1 diabetes autoantigens IA-2, IA-2?, and GAD65.

ABSTRACT: Islet antigen (IA)-2, IA-2?, and glutamate decarboxylase (GAD65) are major autoantigens in type 1 diabetes (T1D). Autoantibodies to these autoantigens appear years before disease onset and are widely used as predictive markers. Little is known, however, about what regulates the expression of these autoantigens. The present experiments were initiated to test the hypothesis that microRNAs (miRNAs) can target and affect the levels of these autoantigens. Bioinformatics was used to identify miRNAs predicted to target the mRNAs coding IA-2, IA-2?, and GAD65. RNA interference for the miRNA processing enzyme Dicer1 and individual miRNA mimics and inhibitors were used to confirm the effect in mouse islets and MIN6 cells. We show that the imprinted 14q32 miRNA cluster contains 56 miRNAs, 32 of which are predicted to target the mRNAs of T1D autoantigens and 12 of which are glucose-sensitive. Using miRNA mimics and inhibitors, we confirmed that at least 7 of these miRNAs modulate the mRNA levels of the T1D autoantigens. Dicer1 knockdown significantly reduced the mRNA levels of all 3 autoantigens, further confirming the importance of miRNAs in this regulation. We conclude that miRNAs are involved in regulating the expression of the major T1D autoantigens.

SUBMITTER: Abuhatzira L

PROVIDER: S-EPMC4566937 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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Multiple microRNAs within the 14q32 cluster target the mRNAs of major type 1 diabetes autoantigens IA-2, IA-2β, and GAD65.

Abuhatzira Liron L Xu Huanyu H Tahhan Georges G Boulougoura Afroditi A Schäffer Alejandro A AA Notkins Abner L AL

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20150706 10

Islet antigen (IA)-2, IA-2β, and glutamate decarboxylase (GAD65) are major autoantigens in type 1 diabetes (T1D). Autoantibodies to these autoantigens appear years before disease onset and are widely used as predictive markers. Little is known, however, about what regulates the expression of these autoantigens. The present experiments were initiated to test the hypothesis that microRNAs (miRNAs) can target and affect the levels of these autoantigens. Bioinformatics was used to identify miRNAs pr ...[more]

PMID: 26148972

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Project description:Background: We previously described that PECAM+ circulating endothelial microparticles (EMPs) are elevated in bicuspid aortic valve (BAV) disease as a manifestation of endothelial damage. In this study, we hypothesized that this endothelial damage, is functionally related to the secretion of a specific pattern of EMP-associated miRNAs. Methods: We used a bioinformatics approach to correlate the PECAM+ EMP levels with the miRNA expression profile in plasma in healthy individuals and BAV patients (n = 36). In addition, using the miRNAs that were significantly associated with PECAM+ EMP levels, we inferred a miRNA co-expression network using a Gaussian graphical modeling approach to identify highly co-expressed miRNAs or miRNA clusters whose expression could functionally regulate endothelial damage. Results: We identified a co-expression network composed of 131 miRNAs whose circulating expression was significantly associated with PECAM+ EMP levels. Using a topological analysis, we found that miR-494 was the most important hub within the co-expression network. Furthermore, through positional gene enrichment analysis, we identified a cluster of 19 highly co-expressed miRNAs, including miR-494, that was located in the 14q32 locus on chromosome 14 (p = 1.9 × 10-7). We evaluated the putative biological role of this miRNA cluster by determining the biological significance of the genes targeted by the cluster using functional enrichment analysis. We found that this cluster was involved in the regulation of genes with various functions, specifically the "cellular nitrogen compound metabolic process" (p = 2.34 × 10-145), "immune system process" (p = 2.57 × 10-6), and "extracellular matrix organization" (p = 8.14 × 10-5) gene ontology terms and the "TGF-β signaling pathway" KEGG term (p = 2.59 × 10-8). Conclusions: Using an integrative bioinformatics approach, we identified the circulating miRNA expression profile associated with secreted PECAM+ EMPs in BAV disease. Additionally, we identified a highly co-expressed miRNA cluster that could mediate crucial biological processes in BAV disease, including the nitrogen signaling pathway, cellular activation, and the transforming growth factor beta signaling pathway. In conclusion, EMP-associated and co-expressed miRNAs could act as molecular effectors of the intercellular communication carried out by EMPs in response to endothelial damage.

Dataset Information

Multiple microRNAs within the 14q32 cluster target the mRNAs of major type 1 diabetes autoantigens IA-2, IA-2?, and GAD65.

Publications

Multiple microRNAs within the 14q32 cluster target the mRNAs of major type 1 diabetes autoantigens IA-2, IA-2β, and GAD65.

Similar Datasets

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